The present invention relates to a process for preparing 1-(4xe2x80x2-fluorophenyl)-1-(3-dimethylaminopropyl)-5-phthalanecarbonitrile (xe2x80x9ccitalopramxe2x80x9d) or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to an improved process for preparing citalopram hydrobromide from 5-bromophthalide.
Citalopram is a bicyclic phthalane derivative of the formula (I), which has been found to have useful therapeutic activity, particularly as an antidepressant. 
The preparation of citalopram and its hydrobromide salt from 5-bromophthalide and the properties of such compounds was first reported in U.S. Pat. No. 4,136,193, which corresponds to German Offenlegungsschrift No. 2,657,013. U.S. Pat. No. 4,136,193 discloses a synthesis of citalopram starting from 5-bromophthalide, which involves the use of two successive Grignard reactions. In a first reaction, a Grignard reagent prepared from p-fluorobromobenzene and magnesium turnings in ether was reacted with 5-bromophthalide to give 2-hydroxymethyl-4-bromo-4xe2x80x2-fluorobenzophenone. The latter was isolated as a crude oil before, in a second reaction, being added to N,N-dimethylaminopropylymagnesium chloride to give (4-bromo-2-(hydroxymethyl)phenyl)-(4xe2x80x2-fluorophenyl)-(3-dimethylaminopropyl)-methanol. The latter was dehydrated with 60 aqueous phosphoric acid to yield 1-(4xe2x80x2-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane, which was then refluxed with cupric cyanide in dimethylformamide to give citalopram.
A number of other processes have been reported for the manufacture of citalopram hydrobromide. Subsequent patents indicate that 5-cyanophthalide should be used as a raw starting material giving the reason that the method disclosed in U.S. Pat. No. 4,136,193 is not a good one because of the inherent problems involved, the main difficulties faced being due to the Grignard Reactions and the replacement of the bromo group by the cyano group. It is an object of the present invention to try to resolve such difficulties by the use of specific reagents and simple techniques.
Moreover, in U.S. Pat. No. 4,136,193, process details were not discussed in any detail. It is an object of the present invention to describe not only the manufacturing technology in detail, but also the purification carried out at each stage to achieve citalopram of pharmaceutical grade purity, as well as additional purification methods using water as a solvent. The present invention therefore relates to an improved process for the manufacture of citalopram hydrobromide and other salts of citalopram, such as its hydrochloride, acetate and oxalate, from 5-bromo- and other 5-halophthalides.